TARGETING CANCER
The before-and-after CAT scans are dramatic: The first shows a tumor lodged deep in the patient’s head, his right eye protruding from the pressure. The second shows a return to normal.
The patient was one of the first to be treated in clinical trials here at the world’s only heavy-ion accelerator built specifically for cancer therapy--an enormous high-tech apparatus several basketball courts long that can zap tumors with carefully targeted beams of particles.
Three years after his treatment, the 77-year-old man “is still alive, and there’s no problem,” said Hirohiko Tsuji, director of radiation medicine at Japan’s National Institute of Radiological Sciences, which runs the unique facility in this Tokyo suburb.
Clinical trials on a limited
number of patients with inoperable cancers started in 1994 at the experimental center, called the Heavy-Ion Medical Accelerator in Chiba, or HIMAC.
Testing so far is focused on toxicity studies, not comparative cure rates. Initial results on the first 145 patients indicate the treatment is generally safe at the doses used so far and that it is effective for some types of cancers, Tsuji said.
HIMAC works by stripping off the negatively charged electrons from carbon atoms, accelerating the atoms’ positively charged nuclei--the atoms’ cores--to 65% of the speed of light, then shooting them into tumors where they so disrupt molecular structures that cancer cells die.
The key advantage of this treatment is that the destructive power of the heavy-ion beam can be delivered almost entirely to the tumor itself, thus avoiding damage to surrounding tissue.
Tumors were destroyed, with no signs of regrowth six months after treatment, in 123 out of the 145 patients treated from June 1994 to August 1996, according to institute statistics. Among the first 43 patients, 29 showed no signs of recurrence 18 months after treatment.
These statistics look only at the specific tumors that were treated, and in some patients the cancers had already spread, so the figures are not cure rates. One of the weak points of heavy-ion therapy is that it is of little use in cases where cancer has already metastasized.
“We do not think it is a miracle bullet,” Tsuji stressed. “It has advantages and disadvantages.”
The technology builds on work started at the Lawrence Berkeley Laboratory in Berkeley, where from 1977 to 1992, researchers treated about 1,300 patients with an accelerator built in 1954.
The Berkeley machine had produced many ground-breaking discoveries in nuclear physics--and four Nobel prizes--before being turned to cancer research. It was shut down in a 1992 cost-cutting move by the Energy Department, to save about $15 million a year.
The work at Berkeley, which used less sophisticated equipment than that at HIMAC, indicated that heavy-ion cancer therapy held promise for treatment of some kinds of inoperable tumors. The decision to build HIMAC was based partly on the Berkeley results.
After it opened in 1994, HIMAC was the only facility in the world offering heavy-ion therapy. An existing heavy-ion research center in Darmstadt, Germany, is also gearing up to treat cancer patients.
Most U.S. researchers have felt that although the work at Lawrence Berkeley was interesting, the enormous expense of building heavy-ion accelerators to treat cancer couldn’t be justified when compared with alternative uses.
Much less expensive--but perhaps less effective--proton accelerators are in use at a few centers in the United States, mainly Loma Linda Medical Center and Massachusetts General Hospital in Boston. These work according to similar principles as HIMAC but use smaller particles--protons--that pack less punch.
Conventional radiation therapy for cancer uses X-rays or gamma rays, which are forms of electromagnetic radiation that have no mass. Their destructive energy cannot be focused as directly as is possible with particle beams. That means X-ray or gamma ray doses powerful enough to kill a tumor may also have severe side effects.
There is little doubt that in terms of physics and biology, heavy ions are better than protons for killing cancer tumors, said Joseph R. Castro, professor of radiation oncology at UC San Francisco’s School of Medicine, who headed the studies at Lawrence Berkeley.
“The research question is, ‘Is it worth the extra money?’ ” Castro said. “I think it’s premature to make any judgment about how valuable heavy-ion treatment will be. . . . If the Japanese or the Germans were to show over the next five years that this could make a major impact on one or more tumor sites, then I think you would see some consideration of getting this started in the U.S. again.”
Despite the potential advantages, a facility such as HIMAC is so expensive that even in Japan it probably would never have been built if its funding had had to come from the nation’s medical or cancer research establishment.
But HIMAC is the creation of Japan’s Science and Technology Agency, which has its own funding for high-tech nuclear research. It decided to build HIMAC as a cancer treatment facility, with an attached 100-bed hospital and the capacity to treat about 1,000 patients per year.
The expense was justified partly with the idea that if the experiments ultimately lead nowhere, the $270-million machine can always be put to use for research into subatomic nuclear physics. It is already being used on evenings and weekends for such nonmedical purposes.
The National Institute of Radiological Sciences was a natural choice because of its unique history as a center for study of the effects of radiation on humans.
Founding of the institute was triggered by a 1954 U.S. nuclear test on Bikini Atoll in the South Pacific that showered a Japanese fishing boat crew with radioactive fallout. Coming against the backdrop of the 1945 atomic bombings of Hiroshima and Nagasaki, the Bikini incident prompted the Japanese government to set up the institute in 1957 to study the effects of radiation and seek more effective treatments.
This special history and the bureaucratic structure surrounding the HIMAC project help explain why Japan has jumped to the forefront in the field. Annual operating costs for the accelerator run about $45 million, but that doesn’t cut into other health research expenditures because other programs come under different ministries, Tsuji said.
“It is fortunate for us we don’t have to compete with other oncologists,” he said. “That could be the difference with the United States.”
The doctors and engineers at HIMAC clearly believe in the promise of heavy-ion treatment, but at the same time try not to make excessive claims for it. Tsuji stressed that the major purpose of the initial clinical trials “is to find out toxicity--in other words, the side effects of carbon-ion therapy.”
“So far, we think that carbon ions are very safe as far as the doses we are using. We have been escalating the dose at 10% intervals.”
In general, doctors expect that lower doses will create fewer side effects but be less effective in controlling tumors, while higher doses will do a better job of killing cancers but also produce more side effects. The institute has not yet determined what the ideal dosage levels are for various types of cancers, and there have not yet been controlled studies on the effectiveness of the treatment, Tsuji said.
Patients typically receive about 16 treatments, each consisting of two or three minutes of irradiation, spread over a month, Tsuji said. Cancers that have been treated include those of the head, neck, brain, lung, liver, prostate, uterus and bone.
HIMAC works this way, Kawachi explained:
Ions are created by stripping some of the electrons from carbon atoms; they are then fed into a linear accelerator, which uses pulsating electric fields to accelerate the ions to 11% of the speed of light.
The ions are then shot through a thin foil that strips off their remaining electrons, leaving only the positively charged cores of the atoms. The beam of carbon nuclei enters one of two synchrotrons, circular accelerators that use electromagnets to control the particle beam and electric fields to boost its speed.
The particles circle the 425-foot circumference of the synchrotron 800,000 times in two-thirds of a second, reaching about 65% of the speed of light. One synchrotron produces a vertical beam, the other produces a horizontal beam; doctors in three treatment rooms can choose one or both of the beams.
Special devices modify the shape and speed of the carbon-ion beams to fit the size and location of a patient’s tumor. The beams shoot through the patient’s healthy flesh or organs with virtually no effect. As the positively charged particles slow and stop inside the tumor, each one attracts toward it huge numbers of negatively charged electrons from atoms in nearby cancer cells. The molecular disruption is enough to kill those cells--and often the entire tumor.
There is enough optimism in Japan about the therapy that Hyogo Prefecture, which includes the West Japan city of Kobe, has begun construction of a $245-million particle-beam cancer treatment facility, which is due to open by 2002. Plans call for the initial use only of proton beam therapy, but the center will be able to provide carbon-ion therapy as well if the experiments at HIMAC prove successful.
If, over the next five to 10 years, HIMAC can show that heavy-ion therapy is the best treatment for even a few specific types of tumors, patients with those kinds of cancer may be brought here from throughout Japan, Tsuji said.
But the goal is to discover sufficiently effective therapy techniques to trigger construction of more such facilities in Japan and perhaps around the world.
“This is a research institution,” Tsuji explained. “If we can give the result [that] ‘this type of treatment could be used for this type of tumor,’ then we can ask other cancer centers to build similar, more compact machines of this type.” Just a few heavy-ion accelerators, he said, “could be enough for Japan.”
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TARGETING CANCER
Early clinical trials of the use of heavy-ion radiation as a cancer treatment have shown promise. An experimental facility near Tokyo uses technology originally developed for the study of nuclear physics to blast inoperable cancer tumors with beams of carbon ions.
1. Positively charged nuclei of carbon atoms are boosted to 65% of the speed of light through linear accelerators and synchrotrons.
2. Controlled by powerful magnetic fields, vertical and horizontal beams of the particles are directed into treatment rooms.
3. Special devices designed according to the size and location of a patient’s tumor modify the shape and speed of the beams.
4. The particles pass through healthy flesh or organs at such high speed that they cause no damage.
5. As the positively charged particles slow down and stop inside the tumor, each one attracts toward it huge numbers of negatively charged electrons from atoms in nearby cancer cells. The molecular disruption is so great that those cells and often the entire tumor are killed.
